One of the major concerns in the use of opioid drugs is tolerance observed after repeated opioid administration. In animals, analgesic tolerance induced by mu-opioid agonists is associated with receptor down- regulation as well as receptor uncoupling. The later involves a decrease in the number of functional high affinity receptor without a net loss of total receptor number. Because of a lack of high-affinity, high- selectivity delta-agonists in the past, it was not known whether delta- agonists will similarly induce tolerance after continued use, and if the mechanism (s) of opioid receptor down-regulation and uncoupling will be also observed with delta-receptor tolerance. This study is aimed at investigation of delta-receptor activated spinal analgesia and associated tolerance in rats with newly available delta-agonists. Cross tolerance between mu- and delta-opioid receptors has been observed and the phenomenon is little studied and understood. In the past, the overlapping receptor activity of available opioid drugs such as morphine and DADLE made the study of cross-tolerance difficult. With the synthesis and availability of delta-receptor-selective drugs deltorphin II and BW373U86 it is now feasible to examine opioid cross-tolerance in detail. This proposal will study the rate, degree and reversibility of tolerance as well as cross-tolerance with the rat spinal analgesic model, and examine whether cross-tolerance to opioids in rats is also associated with receptor down-regulation and/or uncoupling. The information generated from the tolerance and cross-tolerance studies will be used to establish a treatment regimen to test the hypothesis that opioid tolerance can be avoided by alternating mu- and delta-drugs in a continuous intrathecal infusion model. The goal is to lay the experimental basis for a new therapeutic approach to the treatment of chronic pain in human.